Xenazine

CLINICAL PHARMACOLOGY

Mechanism of Action

The precise mechanism by which XENAZINE (tetrabenazine)
exerts its anti-chorea effects is unknown but is believed to be related to its
effect as a reversible depletor of monoamines (such as dopamine, serotonin,
norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly
inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100
nM), resulting in decreased uptake of monoamines into synaptic vesicles and
depletion of monoamine stores. Human VMAT2 is also inhibited by
dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α-
and β-HTBZ, major circulating metabolites in humans, exhibit high in vitro
binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding
affinity at the dopamine D2 receptor (Ki = 2100 nM).

Pharmacodynamics

QTc Prolongation

The effect of a single 25 or 50 mg dose of XENAZINE on the
QT interval was studied in a randomized, double-blind, placebo controlled
crossover study in healthy male and female subjects with moxifloxacin as a
positive control. At 50 mg, XENAZINE caused an approximately 8 msec mean
increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that
inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of XENAZINE
does not further increase the effect on the QTc interval. Effects at higher
exposures to either XENAZINE or its metabolites have not been evaluated [see WARNINGS
AND PRECAUTIONS, DRUG INTERACTIONS, and Use in Specific
Populations].

Melanin Binding

Tetrabenazine or its metabolites bind to melanin-containing
tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of
radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at
21 days post dosing [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

Following oral administration of tetrabenazine, the extent
of absorption is at least 75%. After single oral doses ranging from 12.5 to 50
mg, plasma concentrations of tetrabenazine are generally below the limit of
detection because of the rapid and extensive hepatic metabolism of tetrabenazine
by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ.
α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma
concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½
hours post-dosing. α-HTBZ is subsequently metabolized to a minor
metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized
to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which
Cmax is reached approximately 2 hours post-dosing.

Food Effects

The effects of food on the bioavailability of XENAZINE were
studied in subjects administered a single dose with and without food. Food had
no effect on mean plasma concentrations, Cmax, or the area under the
concentration time course (AUC) of α-HTBZ or β-HTBZ. XENAZINE can, therefore,
be administered without regard to meals.

Distribution

Results of PET-scan studies in humans show that
radioactivity is rapidly distributed to the brain following intravenous
injection of 11C-labeled tetrabenazine or α-HTBZ, with the highest binding
in the striatum and lowest binding in the cortex.

The in vitro protein binding of tetrabenazine, α-HTBZ,
and β-HTBZ was examined in human plasma for concentrations ranging from 50
to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding
ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.

Metabolism

After oral administration in humans, at least 19 metabolites
of tetrabenazine have been identified. α-HTBZ, β-HTBZ and
9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are,
subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and
β- HTBZ are formed by carbonyl reductase that occurs mainly in the liver.
α-HTBZ is Odealkylated by CYP450 enzymes, principally CYP2D6, with some
contribution of CYP1A2 to form 9-desmethyl-α-DHTBZ, a minor metabolite.
β-HTBZ is O-dealkylated principally by CYP2D6 to form
9-desmethyl-β-DHTBZ.

The results of in vitro studies do not suggest that
tetrabenazine, α-HTBZ, or β-HTBZ are likely to result in clinically
significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its
α- or β-HTBZ metabolites are likely to result in clinically
significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.

Neither tetrabenazine nor its α- or β-HTBZ
metabolites is likely to be a substrate or inhibitor of P-glycoprotein at
clinically relevant concentrations in vivo.

No in vitro metabolism studies have been conducted to
evaluate the potential of the 9-desmethyl- β-DHTBZ metabolite to interact
with other drugs. The activity of this metabolite relative to the parent drug
is unknown.

Elimination

After oral administration, tetrabenazine is extensively
hepatically metabolized, and the metabolites are primarily renally eliminated.
α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7
hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy
volunteers, approximately 75% of the dose was excreted in the urine and fecal
recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine
has not been found in human urine. Urinary excretion of α-HTBZ or
β-HTBZ accounted for less than 10% of the administered dose. Circulating
metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites
as well as products of oxidative metabolism, account for the majority of metabolites
in the urine.

Specific Populations

Pediatric Patient

The pharmacokinetics of XENAZINE and its primary metabolites
have not been studied in pediatric subjects [see Use In Specific Populations].

Geriatric Patient

The pharmacokinetics of XENAZINE and its primary metabolites
have not been formally studied in geriatric subjects [see Use in Specific
Populations].

Gender

There is no apparent effect of gender on the pharmacokinetics
of α-HTBZ or β-HTBZ.

Race

Racial differences in the pharmacokinetics of XENAZINE and its
primary metabolites have not been formally studied.

Patients with Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of
XENAZINE and its primary metabolites has not been studied.

Patients with Hepatic Impairment

The disposition of tetrabenazine was compared in 12 patients
with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and
12 age- and gender-matched subjects with normal hepatic function who received a
single 25 mg dose of tetrabenazine. In patients with hepatic impairment,
tetrabenazine plasma concentrations were similar to or higher than
concentrations of α-HTBZ, reflecting the markedly decreased metabolism of
tetrabenazine to α-HTBZ. The mean tetrabenazine Cmax in hepatically
impaired subjects was approximately 7- to 190-fold higher than the detectable
peak concentrations in healthy subjects. The elimination half-life of
tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours.
The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was
slightly delayed in subjects with hepatic impairment compared to age-matched
controls (1.75 hrs vs. 1.0 hrs), and the elimination half lives of the
α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours,
respectively.

The exposure to α-HTBZ and β-HTBZ was
approximately 30-39% greater in patients with liver impairment than in
age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine
and other circulating metabolites are unknown so that it is not possible to
adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use.
Therefore, tetrabenazine is contraindicated in patients with hepatic
impairment. [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, and Use In Specific Populations].

Poor Metabolizers

Although the pharmacokinetics of XENAZINE and its
metabolites in subjects who do not express the drug metabolizing enzyme,
CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is
likely that the exposure to α-HTBZ and β-HTBZ would be increased
similar to that observed in patients taking strong CYP2D6 inhibitors (3- and
9-fold, respectively). Patients who are PMs should not be given doses greater
than 50 mg per day and the maximum recommended single dose is 25 mg [see DOSAGE
AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Use in Specific
Populations].

Drug Interactions

CYP2D6 Inhibitors

In vitro studies indicate that α-HTBZ and
β-HTBZ are substrates for CYP2D6. The effect of CYP2D6 inhibition on the
pharmacokinetics of tetrabenazine and its metabolites was studied in 25 healthy
subjects following a single 50 mg dose of tetrabenazine given after 10 days of administration
of the strong CYP2D6 inhibitor paroxetine 20 mg daily. There was an approximately
30% increase in Cmax and an approximately 3-fold increase in AUC for
α-HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine
given alone. For β-HTBZ, the Cmax and AUC were increased 2.4- and 9-fold, respectively,
in subjects given paroxetine prior to tetrabenazine given alone. The
elimination half-life of α-HTBZ and β-HTBZ was approximately 14 hours
when tetrabenazine was given with paroxetine.

Digoxin

Digoxin is a substrate for P-glycoprotein. A study in
healthy volunteers showed that XENAZINE (25 mg twice daily for 3 days) did not
affect the bioavailability of digoxin, suggesting that at this dose, XENAZINE
does not affect P-glycoprotein in the intestinal tract. In vitro studies also
do not suggest that XENAZINE or its metabolites are P-glycoprotein inhibitors.

Monoamine Oxidase Inhibitors (MAOIs)

XENAZINE is contraindicated in patients taking MAOIs.
XENAZINE should not be used in combination with an MAOI, or within a minimum of
14 days of discontinuing therapy with an MAOI [see CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, and DRUG INTERACTIONS].

Clinical Studies

Study 1

The efficacy of XENAZINE as a treatment for the chorea of
Huntington's disease was established primarily in a randomized, double-blind,
placebo-controlled multi-center trial (Study 1) conducted in ambulatory
patients with a diagnosis of HD. The diagnosis of HD was based on family
history, neurological exam, and genetic testing. Treatment duration was 12
weeks, including a 7-week dose titration period and a 5-week maintenance period
followed by a 1-week washout. The dose of XENAZINE was started at 12.5 mg per
day and titrated upward at weekly intervals in 12.5 mg increments until
satisfactory control of chorea was achieved, until intolerable side effects
occurred, or until a maximal dose of 100 mg per day was reached.

The primary efficacy endpoint was the Total Chorea Score, an
item of the Unified Huntington's Disease Rating Scale (UHDRS). On this scale,
chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different
parts of the body. The total score ranges from 0 to 28.

As shown in Figure 1, Total Chorea Scores for subjects in
the drug group declined by an estimated 5.0 units during maintenance therapy
(average of Week 9 and Week 12 scores versus baseline), compared to an
estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was
statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation
of the study medication), the Total Chorea Scores of subjects receiving XENAZINE
returned to baseline.

Figure 2 illustrates the cumulative percentages of patients
from the XENAZINE and placebo treatment groups who achieved the level of
reduction in the Total Chorea Score shown on the X axis. The left-ward shift of
the curve (toward greater improvement) for XENAZINE-treated patients indicates
that these patients were more likely to have any given degree of improvement in
chorea score. Thus, for example, about 7% of placebo patients had a 6-point or
greater improvement compared to 50% of XENAZINE-treated patients. The
percentage of patients achieving reductions of at least 10, 6, and 3-points
from baseline to Week 12 are shown in the inset table.

Figure 2: Cumulative Percentage of Patients with
Specified Changes from Baseline in Total Chorea Score.

The Percentages of Randomized Patients within each treatment
group who completed Study 1 were: Placebo 97%, Tetrabenazine 91%.

A Physician-rated Clinical Global Impression (CGI) favored
XENAZINE statistically. In general, measures of functional capacity and
cognition showed no difference between XENAZINE and placebo. However, one
functional measure (Part 4 of the UHDRS), a 25-item scale assessing the
capacity for patients to perform certain activities of daily living, showed a decrement
for patients treated with XENAZINE compared to placebo, a difference that was nominally
statistically significant. A 3-item cognitive battery specifically developed to
assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed
a decrement for patients treated with XENAZINE compared to placebo, but the
difference was not statistically significant.

Study 2

A second controlled study was performed in patients who had
been treated with open-label XENAZINE for at least 2 months (mean duration of
treatment was 2 years). They were randomized to continuation of XENAZINE at the
same dose (n=12) or to placebo (n=6) for three days, at which time their chorea
scores were compared. Although the comparison did not reach statistical
significance (p=0.1), the estimate of the treatment effect was similar to that
seen in Study 1 (about 3.5 units).

Last reviewed on RxList: 10/29/2012
This monograph has been modified to include the generic and brand name in many instances.